Antineutrophil cytoplasmic antibodies: major autoantigens, pathophysiology, and disease associations.

Antineutrophil cytoplasmic antibodies (ANCA) are important serological markers for the primary systemic vasculitides, including microscopic polyarteritis and necrotizing crescentic glomerulonephritis. Numerous reports have established the clinical utility of ANCA titer in monitoring disease activity, relapses, and response to treatment. ANCA, detected by indirect immunofluorescence (IIF) assays using patient's serum and ethanol-fixed human neutrophils, produce two common fluorescent staining patterns: cytoplasmic (C-ANCA), involving a 29-kD neutral serine protease termed proteinase 3 (PR3), and perinuclear (P-ANCA), the result mainly of myeloperoxidase (MPO), but occasionally by other components of the azurophilic granules including lysozyme, elastase, cathepsins, and lactoferrin. Some sera contain granulocyte-specific antinuclear antibodies (GS-ANA), which require formaldehyde fixation of neutrophils to cross link cytoplasmic antigens for distinguishing between ANCA and the GS-ANA by IIF. Positive IIF is confirmed by Western blot analysis or specific enzyme-linked immunosorbent assay for PR3, MPO, and other neutrophil granule antigens. The C-ANCA pattern is highly specific for Wegener's granulomatosis, a disease characterized by granulomatous inflammation, necrotizing and crescentic glomerulonephritis, and vasculitis; P-ANCA is found in sera of individuals with vasculitis, glomerulonephritis, and several other diseases. ANCA are predominantly immunoglobulin (Ig)G isotype, but may be IgM and IgA. Various pathophysiologic mechanisms have been proposed involving ANCA-mediated neutrophil activation in a hypothetical model of vasculitic diseases: positive signals via the FcgammaRII (CD32) receptor after IgG-ANCA binding to membrane-associated PR3, relevant cytokines, production of adhesion molecules on both activated neutrophils and endothelial cells, and the release of neutrophil reactive oxygen species and degranulation causing endothelial cell damage. Interference of C-ANCA with PR3 proteolysis and PR3 inhibition physiologically by the alpha1-proteinase inhibitor may have a pathogenic role. No convincing data have been reported for the existence of autoreactive T lymphocytes reactive to any degree with the neutrophil azurophilic enzymes. Studies of various drug- and infectious agent-related diseases and ANCA may contribute to understanding the mechanism(s) involved in some vasculitides.

Hematologic disorders in rheumatic diseases.

Hematologic diseases often have musculoskeletal manifestations, and their diagnosis and treatment are relevant to the rheumatologist. Primary disorders of the blood such as hemophilia or sickle-cell disease may affect bones, joints, or soft tissues. Recent clinical, epidemiologic, and radiographic studies are reviewed.

Sickle-cell disease, hemophilia, and hematology.

Primary hematologic disorders and the hematologic problems associated with systemic rheumatologic disease have widespread and significant implications for the clinical management of rheumatic disease. This article reviews recently published information on the epidemiology, pathophysiology, and management of hemoglobinopathies, hemophilia, and other hematologic pathologies associated with significant rheumatologic manifestations.

Nonneoplastic hematologic disease.

Recent literature on nonneoplastic hematologic disease in the rheumatic disorders has been reviewed, and current concepts on the anemia of rheumatoid arthritis and its treatment have been expanded. The anemia of chronic renal failure and of acquired immunodeficiency syndrome has responded to treatment with recombinant human erythropoietin. Recent studies document that the anemia of rheumatoid disease can also be alleviated with intermittent intravenous or subcutaneous administration of erythropoietin without apparent adverse reaction. However, no improvement is evident in the underlying rheumatoid disease or functional abilities of these patients. Further data are needed to determine the utility of erythropoietin therapy in rheumatoid arthritis and in other rheumatic diseases. Other mechanisms of anemia of rheumatoid disease have been studied, and as the underlying defects become known, other therapies may become available to patients with rheumatoid arthritis and other rheumatic diseases.

Sarcoidosis: clinical manifestations, epidemiology, therapy, and pathophysiology.

Sarcoidosis is an idiopathic granulomatous disease involving one or more multiple organ systems, characterized by the histologic finding of noncaseating epithelioid cell granulomas. The disease has a predilection for intrathoracic structures; the musculoskeletal system is less frequently involved. Most osseous lesions in sarcoidosis are visible in the small joints of the hands and feet. Articular disease may present as an acute or chronic polyarthritis. Muscle involvement in sarcoidosis is generally asymptomatic. Neurologic findings of the central and peripheral nervous systems may occur in sarcoidosis. Subcutaneous nodules are of diagnostic value. Sarcoid vasculitis may involve small and large blood vessels. Sarcoidosis of the exocrine glands may mimic Sjögren's syndrome. Spontaneous remission of disease often occurs. Treatment with nonsteroidal anti-inflammatory agents, corticosteroids, antimalarials, radiation therapy, and immune-modulating drugs may be beneficial in the treatment of sarcoidosis.

Adverse reactions with oral and parenteral gold preparations.

Auranofin (triethylphosphine gold), an oral gold preparation, has recently been made available, and along with injectable gold preparations, is of therapeutic value for rheumatoid arthritis. Serious gold toxicity is uncommon, and drug-related deaths rare. Many potential adverse reactions are similar, including dermatitis, stomatitis, thrombocytopenia, leucopenia, and proteinuria, generally with increased incidence in the injectable gold-treated patients. Oral gold is associated with benign lower gastrointestinal side effects, including diarrhoea, loose stools and abdominal cramps that are often dose-related and resolve spontaneously. The incidence of severe reactions such as thrombocytopenia, aplastic anaemia and exfoliative dermatitis is lower with oral gold than injectable preparations, and contributes to a superior risk-benefit ratio. The treatment of gold toxicity depends on the type and extent of organ involvement.

The lupus activity criteria count (LACC).

A single clinical and laboratory assessment from each of 50 randomly chosen patients with systemic lupus erythematosus followed in a prospective study were evaluated for disease activity by 3 individual rheumatologists. Of the 50 assessments, 24 were considered to be active, 12 possibly active and 14 inactive. The 38 assessments that were clearly active or inactive were then analyzed. Clusters of variables were chosen for clinical relevance and association with activity, and 7 highly associated variables were combined into the lupus activity criteria count. Analysis of these criteria in the 50 assessments revealed that the presence of any 2 correctly predicted active disease in 100% of cases. This activity criteria count was then validated using a second sample of 50 assessments.

Chronic adhesive lupus serositis as a complication of systemic lupus erythematosus. Refractory chest pain and small-bowel obstruction.

Serious clinical sequelae of lupus serositis are uncommon and rarely a cause of morbidity. We describe two patients, one with chronic adhesive pericarditis and one with extensive small-bowel adhesions due to lupus peritonitis. In both, delayed institution of adequate prednisone therapy may have played a contributing role.

Haemostatic abnormalities in systemic lupus erythematosus.

Coagulation studies were performed in 112 consecutive patients with systemic lupus erythematosus (SLE). Abnormalities of haemostatic function occurred frequently and 96 abnormalities occurred in 64 of 112 (57 per cent) patients. Eighteen patients (16 per cent) had thrombocytopenia, 19 (16.9 per cent) had circulating anticoagulants and 24 had decreased antithrombin III levels. Abnormalities of fibrinogen were found in 28 patients (23 per cent), and abnormalities of platelet factor 3 and 4, indicating in vivo platelet activation occurred in seven patients. In 25 patients two or more abnormalities were detected simultaneously. No haemostatic abnormalities were detected in any of the 50 healthy volunteers who served as controls. Only one patient with thrombocytopenia had petechiae. None of the other patients, even those with multiple defects bled significantly, but several patients had vasculitis and/or phlebitis. There was no correlation between disease activity of SLE and the presence of haemostatic abnormalities, nor was there an association between these abnormalities and specific clinical haematologic manifestations.

Prolonged complete remission in previously severe SLE.

Of 160 patients with systemic lupus erythematosus followed up in a long-term prospective study 4 with previously severe disease are in complete remission and have required no therapy for a median time of 75 months. The 4 females all presented with systemic features and a typical butterfly rash prompting early diagnosis and treatment. All patients have had complete remission of clinical and laboratory features of disease, without maintenance suppressive therapy.

Systemic lupus erythematosus and pregnancy.

In a review of 250 patients with systemic lupus erythematosus (SLE), there were 24 pregnancies among 18 women. Of these, there were 16 completed pregnancies, 1 stillbirth, 1 spontaneous abortion, and 6 therapeutic abortions. Fetal loss, excluding therapeutic abortion, was 16.6%. Of the 13 patients with active disease at conception, SLE remained active in 11, and became inactive in 2. Of the 11 women with inactive disease at conception, disease remained inactive in 10. Even in the cases of previously serious renal or central nervous system involvement, inactive disease at conception was not associated with disease recurrence. Such patients may attempt pregnancy with favorable prognosis for both mother and child.